Journal
CLINICAL CANCER RESEARCH
Volume 27, Issue 18, Pages 5131-5140Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-21-0921
Keywords
-
Categories
Funding
- National Institutes of Health [R01-CA227466, K24-CA169004, T32-CA009207, K30-UL1TR00457, T32-GM007347, F30-HL140756, U54CA217450-01, U01CA224276-01, P30-CA086485, UG1CA233259, U01CA253560-01, R01-CA227237, R01-CA244569]
- Memorial Sloan Kettering Cancer Center Support Grant/Core [P30-CA008748]
- Druckenmiller Center for Lung Cancer Research at Memorial Sloan Kettering Cancer Center
- Vanderbilt Institute for Clinical and Translational Research [UL1TR002243]
- American Diabetes Association [1-19-PDF-131]
- Conquer Cancer Foundation
- Damon Runyon Cancer Research Foundation [CI-98-18]
- Louis B. Mayer Foundation
Ask authors/readers for more resources
Genetic differences in immunity may contribute to toxicity and outcomes with immune checkpoint inhibitor therapy. Thyroid immune-related adverse events were associated with response to anti-PD-1 therapy, and genetic risk for hypothyroidism was associated with the risk of developing thyroid irAEs.
Purpose: Genetic differences in immunity may contribute to toxicity and outcomes with immune checkpoint inhibitor (CPI) therapy, but these relationships are poorly understood. We examined the genetics of thyroid immune- related adverse events (irAE). Experimental Design: In patients with non-small cell lung cancer (NSCLC) treated with CPIs at Memorial Sloan Kettering (MSK) and Vanderbilt University Medical Center (VUMC), we evaluated thyroid irAEs. We typed germline DNA using genome-wide single-nucleotide polymorphism (SNP) arrays and imputed genotypes. Germline SNP imputation was also performed in an independent Dana-Farber Cancer Institute (DFCI) cohort. We developed and validated polygenic risk scores (PRS) for hypothyroidism in noncancer patients using the UK and VUMC BioVU biobanks. These PRSs were applied to thyroid irAEs and CPI response in patients with NSCLC at MSK, VUMC, and DFCI. Results: Among 744 patients at MSK and VUMC, thyroid irAEs occurred in 13% and were associated with improved outcomes [progression-free survival adjusted HR (PFS aHR) = 0.68; 95% confidence interval (CI), 0.52-0.88]. The PRS for hypothyroidism developed from UK Biobank predicted hypothyroidism in the BioVU dataset in noncancer patients [OR per standard deviation (SD) = 1.33, 95% CI, 1.29-1.37; AUROC = 0.6]. The same PRS also predicted development of thyroid irAEs in both independent cohorts of patients treated with CPIs (HR per SD = 1.34; 95% CI, 1.08-1.66; AUROC = 0.6). The results were similar in the DFCI cohort. However, PRS for hypothyroidism did not predict CPI benefit. Conclusions: Thyroid irAEs were associated with response to anti-PD-1 therapy. Genetic risk for hypothyroidism was associated with risk of developing thyroid irAEs. Additional studies are needed to determine whether other irAEs also have shared genetic risk with known autoimmune disorders and the association with treatment response.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available